The TBPod

Today we had the pleasure of being joined by Associate Professor Patrick Phillips from the University of California, who is the Co-Director of the UC Tuberculosis Research Advancement Center, Clinical & Population Health Science Core. Patrick has a wealth of statistical experience and specialises in the design, implementation, and optimisation of clinical trials for new treatments for drug-sensitive and drug-resistant tuberculosis.

Join us as we explore the rapidly evolving field of TB clinical trials and drug development. Discover the latest advancements in surrogate selection, novel Bayesian phase II designs, and the future of adaptive trial designs. We also delve into the critical clinician-statistician interface, highlighting the exciting opportunities for TB clinicians today.

• 10.1186/s12879-022-07846-w

Handaa Enkh Amgalan is an author, TB advocate and director of QA at the International Rescue Committee in Germany who has not only recently spoken at the UN TB High Level Meeting but also written an incredible memoir of her experience being diagnosed with severe pulmonary tuberculosis as a teenager growing up in Mongolia. Handaa gives an incredible insight into what it means to be diagnosed with such a stigmatising disease as a young woman; how it affect her, her family, and her dreams. This amazing story provides us insights into the devastating effects of stigma and sheds light on what we can do as health care workers to better support our patients.

Find Handaa's book at:
- https://www.amazon.co.uk/STIGMATIZED-Mongolian-Journey-Illness-Empowerment-ebook/dp/B0992QBHR2
- https://www.goodreads.com/book/show/58534082-stigmatized

Professor Adrian Martineau from the Queen Mary University London talks to us about the limitations of current latent TB infection diagnosis and how we can do better.  his research into whether we can use fragments of TB DNA found in bone marrow cells to better predict who should be treated with Tuberculosis Preventative Treatment.

REFERENCES
Martineau, Adrian R., et al. "Towards a molecular microbial blood test for tuberculosis infection." International Journal of Infectious Diseases (2024): 106988.

Belay, Mulugeta, et al. "Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts: an observational study." The Lancet Microbe 2.6 (2021): e267-e275.

Repele, Federica, et al. "Detection of Mycobacterium tuberculosis DNA in CD34+ peripheral blood mononuclear cells of adults with tuberculosis infection and disease." International Journal of Infectious Diseases 141 (2024): 106999.

Today we discuss the MTBVAC with Dr Montañés. MTBVAC is an attenuated vaccine from a human mycobacterial isolate which has just progressed to a phase 3 trial and shown very promising results in the phase 2 study. Dr Montañés has been involved in this project for over a decade and has an incredible insight into the development and promise of this vaccine for global TB epidemiology.

References
Martín, Carlos, et al. "MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG." Vaccine 39.50 (2021): 7277-7285.

Achkar, Jacqueline M. "Prospects and challenges of a new live tuberculosis vaccine." The Lancet Respiratory Medicine 7.9 (2019): 723-725.

Arbues, Ainhoa, et al. "Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials." Vaccine 31.42 (2013): 4867-4873.

Tameris, Michele, et al. "Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial." The lancet Respiratory medicine 7.9 (2019): 757-770.

Spertini, François, et al. "Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial." The lancet Respiratory medicine 3.12 (2015): 953-962.

Gonzalo-Asensio, Jesus, et al. "MTBVAC: attenuating the human pathogen of tuberculosis (TB) toward a promising vaccine against the TB epidemic." Frontiers in immunology 8 (2017): 296893.

Prof Greg Fox speaks with Prof Philip Hill about TB household contact tracing and building research capacity in TB.

Prof Hill is an ID specialist and public health physician who did his PhD in TB Epidemiology. He is the current McAuley Chair in International Health as well as being Founding Direction & Co-Director of the Centre for International Health at the University of Otago.

References
1) Martinez, Leonardo, et al. "The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis." The Lancet 395.10228 (2020): 973-984.
2) Hill, Philip C., et al. "Incidence of tuberculosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts." PLoS One 3.1 (2008): e1379.
3) Martinez, Leonardo, et al. "Transmission of Mycobacterium tuberculosis in households and the community: a systematic review and meta-analysis." American journal of epidemiology 185.12 (2017): 1327-1339.
4) Martinez, Leonardo, et al. "Paediatric tuberculosis transmission outside the household: challenging historical paradigms to inform future public health strategies." The Lancet Respiratory Medicine 7.6 (2019): 544-552.
5) Hill, Philip C., and Martin OC Ota. "Tuberculosis case-contact research in endemic tropical settings: design, conduct, and relevance to other infectious diseases." The Lancet infectious diseases 10.10 (2010): 723-732.
6) Alisjahbana, Bachti, et al. "Are neighbourhoods of tuberculosis cases a high-risk population for active intervention? A protocol for tuberculosis active case finding." Plos one 16.8 (2021): e0256043.

Today we speak with Dr Guglielmetti about the END-TB trial which looks at new all oral regimens for MDR-TB.

REFERENCES
1) https://endtb.org/
2) Nyang’wa, Bern-Thomas, et al. "A 24-week, all-oral regimen for rifampin-resistant tuberculosis." New England Journal of Medicine 387.25 (2022): 2331-2343.
3) Conradie, Francesca, et al. "Treatment of highly drug-resistant pulmonary tuberculosis." New England Journal of Medicine 382.10 (2020): 893-902.
4) Diacon, Andreas H., et al. "Multidrug-resistant tuberculosis and culture conversion with bedaquiline." New England Journal of Medicine 371.8 (2014): 723-732.
5) Gler, Maria Tarcela, et al. "Delamanid for multidrug-resistant pulmonary tuberculosis." New England Journal of Medicine 366.23 (2012): 2151-2160.
6) Ahmad, Nafees, et al. "Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis." The Lancet 392.10150 (2018): 821-834.
7) Lan, Zhiyi, et al. "Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis." The Lancet Respiratory Medicine 8.4 (2020): 383-394.
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Today we delve into the world of TB diagnostics and the future of leveraged TB technologies with Dr Morten Ruhwald. Dr Ruhwald is a the head of the TB programme over at FIND, an institution dedicated to accelerating equitable access to reliable diagnosis around the world. Dr Ruhwald elaborates on the current state of TB diagnostics, new clinical strategies, usability factors,  and future TB perspectives.

https://www.finddx.org/what-we-do/programmes/tuberculosis/

https://www.actnet.org.au/

Today we speak with Dr Chris Lowbridge about the amazing work of the TB teams in the Northern Territory. Chris talks about the challenges of controlling tuberculosis across 1.42 million square kilometres, more than 100 local languages, and some very isolated communities.

References
Meumann, Ella M., et al. "Tuberculosis in Australia's tropical north: a population-based genomic epidemiological study." The Lancet Regional Health–Western Pacific 15 (2021).

Vigneswaran, Nilanthy, et al. "Factors leading to diagnostic delay in tuberculosis in the tropical north of Australia." Internal Medicine Journal (2023).

Coorey, N. J., et al. "Risk factors for TB in Australia and their association with delayed treatment completion." The International Journal of Tuberculosis and Lung Disease 26.5 (2022): 399-405.

Francis, J. R., et al. "Multidrug-resistant tuberculosis in Australia, 1998–2012." The international journal of tuberculosis and lung disease 22.3 (2018): 294-299.

Today we speak with Dr Clifton Barry from NIH in Bethesda, Maryland who is head of the most highly cited research group in the field of TB over the past year and has made extraordinary contributions to TB drug development. Dr Barry speaks about his involvement in the PREDICT TB study, the TB Drug Accelerator and some of the most exciting drug developments in recent years.

REFERENCES
Green, Simon R., et al. "Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs." Nature communications 13.1 (2022): 5992.

https://predict-tb.com/

Lange, Christoph, Clifton E. Barry III, and C. Robert Horsburgh Jr. "Treatments of multidrug-resistant tuberculosis: light at the end of the tunnel." American Journal of Respiratory and Critical Care Medicine 205.10 (2022): 1142-1144.

Khan, RM Naseer, et al. "Distributable, metabolic PET reporting of tuberculosis." bioRxiv (2023).

Cole, STea, et al. "Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence." Nature 396.6707 (1998): 190-190.

Finin, Peter, et al. "Chemical approaches to unraveling the biology of mycobacteria." Cell Chemical Biology 30.5 (2023): 420-435.

Libardo, M. Daben J., et al. "Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis." Cell Chemical Biology 28.8 (2021): 1180-1191.

Barry, Clifton E., Helena IM Boshoff, and Cynthia S. Dowd. "Prospects for clinical introduction of nitroimidazole antibiotics for the treatment of tuberculosis." Current pharmaceutical design 10.26 (2004): 3239-3262.

Xie, Yingda L., et al. "Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis." Science Translational Medicine 13.579 (2021): eabd7618.

Today we get an update on where the TB Vaccine pipeline is up to, how TB vaccines work and what exciting candidates might be on the horizon. We speak with Professor Jamie Triccas from the University of Sydney about his work as the principal investigator on the Advancing Vaccine Adjuvant Research for Tuberculosis (AVAR-T) which is an NIH funded project to identify the most promising adjuvant-TB immunogenicity candidates for development.

REFERENCES
Stewart, Erica, James A. Triccas, and Nikolai Petrovsky. "Adjuvant strategies for more effective tuberculosis vaccine immunity." Microorganisms 7.8 (2019): 255.

Counoupas, Claudio, James A. Triccas, and Warwick J. Britton. "Deciphering protective immunity against tuberculosis: implications for vaccine development." Expert Review of Vaccines 18.4 (2019): 353-364.

Triccas, James A., and Jonathan K. Nambiar. "Challenge of developing new tuberculosis vaccines to generate life-long protective immunity." Expert Review of Vaccines 8.7 (2009): 823-825.

Counoupas, Claudio, et al. "Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis." npj Vaccines 5.1 (2020): 105.

Counoupas, Claudio, and James A. Triccas. "The generation of T‐cell memory to protect against tuberculosis." Immunology and Cell Biology 97.7 (2019): 656-663.

Triccas, James A., and Claudio Counoupas. "Novel vaccination approaches to prevent tuberculosis in children." Pneumonia 8 (2016): 1-7.

Counoupas, Claudio, et al. "Protective efficacy of recombinant BCG over-expressing protective, stage-specific antigens of Mycobacterium tuberculosis." Vaccine 36.19 (2018): 2619-2629.

Counoupas, Claudio, et al. "Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice." npj Vaccines 1.1 (2016): 1-11.